The mortality of cardiovascular and cerebrovascular diseases has been the second in the world, wherein thromboembolism is the main reason for the high ratio of morbidity and mortality of cardiovascular and cerebrovascular diseases. Especially with the changes in the way people live and the increasing degree of aging of population, the morbidity of such diseases exhibits a continually increasing tendency. It makes the exploration and research of a medicament for effectively preventing and treating such diseases especially urgent, which is of great significance whether on clinical application or fundamental research.
The clinically used traditional anticoagulant drugs such as heparin, warfarin and hirudin have serious defects in terms of curative effect and safety, which greatly restrains their applications. For example, the heparin must be administered by injection, it fails to act on thrombin in blood clot, and may induce the symptom of thrombocytopenia. Warfarin serves as the sole oral drug, but since there is no definite drug target, the individual responses of anticoagulant differ greatly. There are a lot of influencing factors, and the coagulation function should be monitored. Consequently, it is particularly important to research and develop a novel anticoagulant drug with oral administration activity which is artificially synthesized.
Blood coagulation is the result of complicated action of series of enzymes, wherein a key step is to activate prothrombin to generate thrombin. As a trypsin-like serine protease, the main function of the thrombin is to hydrolyze fibrinogen to generate an insoluble stringy coagulation. Thrombin plays a vital role in cascade reaction of blood coagulation. Thus, the inhibition of the activity of thrombin can blocks the formation of the thrombus. Since its target is definite and different from the target of the traditional anticoagulant drugs, direct thrombin inhibitor (DTI) has a prospect to overcome the limitations in application of the traditional anticoagulant drugs. Obviously, the thrombin inhibitor which makes the treatment of thrombosis convenient, controlled and effectively selective and has oral administration bioactivity represents an attractive object.
Over the past thirty years, tremendous progress has been achieved in the research on the activity of artificially synthesized thrombin inhibitor as anticoagulant, and a large amount of small molecular thrombin inhibitors with high activity and high selectivity have been reported. For example, D-Phe-Pro-Arg-H and Me-D-Phe-Pro-Arg-H of tripeptide aldehyde thrombin inhibitors were reported in U.S. Pat. No. 4,346,078. Recently, D-Phe-Pro-agmatine and its derivatives were described as thrombin inhibitors in U.S. Pat. No. 4,346,078 and WO9311152. Afterwards, a tripeptide inhibitor in which 4-amidinobenzylamine is incorporated to replace agmatine and the like at P1 position was reported in WO9429336 and WO9523609.
In U.S. Pat. No. 4,101,653, Okamoto et al. disclose that series of arginine derivatives are designed and synthesized using N-p-tosyl-arginine methyl ester (TAMA) as a thrombin substrate, and find that argatroban has good inhibitory activity against thrombin. Argatroban is a reversible competitive thrombin inhibitor, which bonds the active position of thrombin to function and has high selectivity for thrombin, and has been approved as an injection on sale in 2001 after the pharmacological clinical research. It is clinically used to treat peripheral thrombosis diseases and acute stroke, and also can be used to treat thrombocytopenia and thrombosis syndrome induced by heparin.
Likewise, Stürzebecher et al. design and synthesize series of benzamidine compounds according to the structure of TAMA, and further modify the structure, finding that the inhibitory activity against thrombin of NAPAP is twice as strong as argatroban (J med chem., 1994, 37, 3889). Series of compounds obtained by changing benzamidine of NAPAP to piperidine-carboxamidine also have higher inhibitory activity against thrombin, wherein napsagatran synthesized by Hoffmann-La Roche Corp. has the strongest activity, and also has an effect on fibrinogen, and on which phase clinical research has been carried out, but its half life is short and the oral bioavailability is poor.
In WO9429336, Astra Corp. discloses a kind of benzamidine analogues, wherein melagatran has powerful effect inhibitory activity against thrombin, and can be safely used for deep venous thrombosis (DVT) if there are no obvious bleeding problems. However its oral bioavailability is low. Ximelagatran as its bipartite prodrug was further synthesized and came into the market in 2004. It is the first oral anticoagulant drug during over 60 years after warfarin. However serious liver damage was clinically found after it came into the market, and its use was terminated in February, 2006.
Moreover, a kind of thrombin inhibitors carrying particular D-diphenylglycine at P3 position is reported in WO9311152, WO9715190, U.S. Pat. No. 5,510,369. It is reported that such compounds have higher antithrombin activity (J Med Chem, 1997, 40, 830), some of which have higher oral bioavailability (J Med Chem, 1997, 40, 3687; J Med Chem, 1997, 40, 3726), compared to D-phenylglycine analogues.
Among the compounds reported, only a few have suitable properties of in vivo pharmacokinetics and pharmacodynamics. So far, the research of thrombin inhibitor is still one of hot research subjects in the field of pharmaceutical chemistry at present.